The hypothesis to be tested in this proposal is that plasma transport factors, in particular the lipoproteins and their apoproteins, are regulatory in the mobilization of peripheral tissue cholesterol and its eventual secretion as either neutral or acidic sterol in bile. The system which will be employed to test this hypothesis will be a recently developed in vitro perfusion of a hind end (representative of peripheral tissue) in tandem with a bile duct canulated liver from an animal of the same specie. The animals to be tested with be in either of three physiologic states with respect to cholesterol: a) in cholesterol balance (on regular chow); b) in positive cholesterol balance (supplementing the diet to either 1 or 2% with cholesterol); and c) in negative cholesterol balance (opening the enterohepatic circulation). Three animal species will be studied because they have remarkable differing responses to enhancing the systemic flux of cholesterol by feeding: 1) the prairie dog, which excretes the sterol briskly in bile and has relatively little hepatic storage; 2) the guinea pig, which excretes the added cholesterol poorly and has enormous hepatic storage; and 3) the rat, which has a response to cholesterol feeding between 1 and 2. The lipoprotein apoprotein responses to cholesterol feeding are also dramatically different; the prairie dog with virtually no Apo E and all AI, II and C and the guinea pig shifting to totally E with the rat between these responses. The in vitro tandem system will permit a) total control of plasma cholesterol transport factors; b) determination of mass and activity gradients across tissue beds, enabling estimates of exchange as opposed to mass movement; c) correlate the controlled plasma factors, tissue perfusate gradient determinations, and tissue mass changes with the delivery of sterol into bile.